KR20020038726A - Compositions Including Modafinil for Treatment of Attention Deficit Hyperactivity Disorder and Mltiple Sclerosis Fatigue - Google Patents

Abstract

Modafinil is effective in improving symptoms of attention deficit hyperactivity disorder and symptoms of multiple sclerosis fatigue. The administration of modafinil is also shown to activate the tuberomamillary neurons of the posterior hypothalamus, and thus exhibits activity in an area of the brain associated with normal wakefulness functions.

Description

Compositions Including Modafinil for Treatment of Attention Deficit Hyperactivity Disorder and Mltiple Sclerosis Fatigue

Attention-deficiency / hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder in children characterized by improperly overactive behavior, impulses, and carelessness. ADHD is estimated to affect 3% to 5% of school-age children. Previously, it was thought that ADHD did not continue past youth. However, recent studies suggest that ADHD persists from adulthood to 10% to 60% of childhood-initiated cases. ADHD persistence is associated with high incidence of psychiatric co-morbidity (eg behavioral disorders, depression and anxiety disorders) as well as high incidence of educational and occupational dysfunction. It is estimated that about 1% to 3% of adults have ADHD symptoms. Adults with ADHD have demographic, psychosocial, psychiatric and cognitive characteristic patterns that reflect proven results in children with these disorders. This further supports the validity of the diagnosis in adults. Core ADHD symptoms in adults include frequent and persistent patterns of inattention / distraction and / or hyperactivity-urge. The most common symptoms in ADHD adults are noticeable inattention, poor concentration, cramping distractions, daydreaming, forgetfulness, and frequent movement of activity. AHDA adults also exhibit low impatience, irritability, impatience and excessive impatience for prominent impulses, invasion, displeasure / stress. Less commonly reported symptoms in adults include hyperactivity, nervousness, or inherent feelings that may be limited to restlessness. In addition to core ADHD symptoms, adults with ADHD exhibit related clinical features such as boredom, social maladjustment, and habitual conflict in social position. This feature may be due to the high incidence of (1) separation and divorce and (2) low educational outcomes and low professional achievement, despite adequate intellectual capacity. In addition, adults with ADHD have a high incidence of substance abuse disorders.

Although the etiology of ADHD is still unclear, changes in dopamine and noradrenaline agonist function appear to be the neurochemical basis of the disorder. Brain positron emission tomography in adults with ADHD showed changes in glucose metabolism in areas of the brain cortex associated with attention and motor activity, such as the frontal lobe. The most common treatments of adult and pediatric ADHD are stimulants (eg, dextroseamphetamine, methylphenidate and femoline). Stimulants are thought to work by increasing the amount of dopamine available at the synapses of neurons. Stimulants seem to do this in several anatomical locations of the brain. Other therapies that have been used include antidepressants (e.g., tricyclic antidepressants such as imipramine and desipramine; novel howl agents such as buproorion and venlafaxine), antihypertensive agents (e.g., clonidine and guanfacin), monoamine oxidase Combination of inhibitors ([MAO's], eg selegiline), amino acids (eg levodopa, phenylalanine and L-tyrosine) and combined pharmacotherapy (eg serotonin-selective reuptake inhibitors and stimulant dosing; or stimulants and catecholaminergic antidepressants Regimen). Bhandary et al., Psychiatric Annuals 27: 545-555, 1997; Wilens et al., J. Clin. Psychopharmacol. 15: 270-279, 1995; Finkel, The Neurologist 3: 31-44, 1997; Miller and Catellanos, Pediatrics in Review 19: 373-384, 1998].

Although stimulants are the most commonly used treatment, about 30% to 50% of adults with ADHD do not respond positively to stimulants, have unacceptable side effects, or stimulant medications exacerbate treatment. You may have concurrent depressive or anxiety disorders that may or may not be effective. Long-term side effects and the use of stimulants in the high-risk substance abuse subpopulation of ADHD remain unstudied and of interest; Thus, there is still a need for non-irritating drug therapies for ADHD.

For a long time, another disease state where the need for non-stimulatory pharmacological therapy has been felt is fatigue associated with multiple sclerosis (MS). Multiple sclerosis is one of the most common neurological disorders in the United States that makes young people incompetent, and an estimated 400,000 people in the United States have it. Although MS can cause various incapacity of the nervous system, such as blindness, paralysis, incoordination and bowel or bladder dysfunction, the lesser known symptom that can be more severely incapacitated is fatigue. In one study involving 656 patients with MS, 78% complained of fatigue, 60% experienced fatigue daily, and 22% experienced confusion in their daily activities [Freal et al., Arch. Phys.Med.Rehabil. 65: 135, 1984]. The National Multiple Sclerosis Society found that 839 patients had only minor minor nervous system damage, despite having had MS for more than 10 years, and fatigue is the most common in this mildly ill group. It was evaluated as a symptom manifested by [Jones, New York: National Multiple Sclerosis Society, Health Services Reseach Report, 1991]. In another study, 40% of MS patients cited fatigue as the most serious symptom of their disease [Murray, Can. J. Neurol. Sci. 12: 251, 1985]. Fatigue is reported to cause at least temporary inability in up to 75% of MS patients; The British MS Association found that the most important symptom of joblessness in this group was fatigue [Rolak, Curr. Neurol. 9; 109, 1989]. In the United States, the prevalence of incompetence associated with MS fatigue has been further emphasized by the inclusion of MS fatigue as a criterion for incompetence under the guidelines outlined by the Social Security Institution.

The mechanism of MS fatigue is poorly understood. This is thought to be due to the increase in energy demand caused by neuroconduction abnormalities and nervous system inability in the central nervous system. Some features of MS fatigue include disturbances in the physical functions and activities of daily living, exacerbation of illness due to heat and exacerbation at the end of the day [Krupp et al., Arch. Neurol. 45: 435, 1988. Agents prescribed for the treatment of MS fatigue include amantadine, femoline and other stimulants. Amantadine has been shown to favor MS fatigue in 79% of patients in a double blind randomized study, but its beneficial mechanism of action is unknown (Krupp et al., Neurology 45: 1956, 1995). Although amantadine has been shown to work in favor of MS fatigue in a rigorous manner, it is reported that the benefit is incomplete in most patients and still a large number of patients do not benefit. The same study of femoline, which is often used in the treatment of MS fatigue, did not show a beneficial effect. Thus, there is a strong need for safe and effective treatment of these debilitating disease states.

Summary of the Invention

The present invention provides a novel use of modafinil in the treatment of attention deficit hyperactivity disorder (ADHD) and in the reduction of fatigue symptoms due to multiple sclerosis (MS).

Studies based on the disclosure of the present invention unexpectedly demonstrated that administering an awakening-promoting dose of modafinil to rats selectively increased the activity of the nodular papillary nucleus (TMN) of the posterior hypothalamus. Modafinil administration reduced neuronal activity at the hypothalamus lateral lateral lateral optic nerve anterior junction (VLPO), which is known to inhibit the activity of arousal-promoting histamine-activated neurons in TMN during sleep. Activation of the histamine agonist pathway by modafinil causes cortical activation and arousal states. Thus, the physiological basis for the awakening-promoting action of modafinil seems to be related to the desuppression of histamine-activated neurons of TMN by inhibitory action in VLPO. This represents the first pharmacological agent known to cause arousal by selective activation of TMN, which was unexpected based on previous literature in this field.

Based on this epidemiologic study, modafinil has significantly different activity from the stimulants commonly used for ADHD and MS fatigue. While modafinil is disclosed herein to promote arousal by selective activation of the hypothalamus nucleus involved in normal arousal states, commonly used psychostimulants (eg, amphetamines) are mesolimbic, nodal papillary and black matter. These are very different drugs because they mostly act by increasing dopamine effector input into the cortex and other brain regions by promoting neurotransmission of dopamine effector neurons in the striatum system. Among these major dopaminergic pathways, the mesenchymal system derived from the ventral overgrowth may be most directly involved in cortical activation, while the nodular papillary and cortical striatum are related to the pituitary and motor functions, respectively. Simultaneously promoting these pathways by amphetamines results in cortical irritation and hyperactivity associated with amphetamine administration. In contrast to the hypothalamic system associated with normal arousal states, the promotion of dopaminergic neurotransmission appears to cause abnormal arousal states in that it is associated with changes in happy mood and perception as well as increased motor activity.

As disclosed herein, it is a surprising finding that nodular papillary neurons in the posterior hypothalamus are activated by modafinil, so new uses of modafinil have been found and such use is an aspect of the present invention. For example, one aspect of the present invention is that modafinil is a novel therapeutic agent that provides significant benefits to patients suffering from ADHD. Because modafinil activates the hypothalamus, and also because of inhibitory histamine effector neuronal pathways from hypothalamic synapses on inhibitory gamma-aminobutyric acid (GABA) frontal lobe neurons, hypothalamic activation may contribute to subsequent cortical cell activation. And provide a mechanism regarding the utility of modafinil in ADHD. In addition, activation of TMN can enhance cortical action by direct histamine agonist. In other words, activation of TMN neurons excites the cortex either directly or indirectly. Insufficient activity in the frontal cortex has been implicated in the pathogenesis of ADHD [Castellanos, F.X., Clinical Pediatrics, 381-393 (1997); Swanson, J. Et al., Current Opinion in Neurobiology, 8: 263-271 (1998); Barkley, R. A., Scientific American, 66-71 (1998).

Thus, aspects of the present invention may be described as a method of treating attention deficit hyperactivity disorder, wherein the method of treatment comprises a composition comprising a modafinil compound in a patient suffering from or susceptible to attention deficit hyperactivity disorder. And administering in an amount effective to ameliorate or prevent symptoms of attention deficit hyperactivity disorder in humans.

A further aspect of the present invention is multiple sclerosis comprising administering a composition containing a modafinil compound to such a patient in an amount effective to ameliorate or prevent symptoms of multiple sclerosis fatigue in a patient suffering from multiple sclerosis fatigue. Associated with fatigue. As used herein, “fatigue” includes the ability to respond to loss of force or stimulation. Here, modafinil has been found to be effective as a treatment to alleviate drowsiness associated with fatigue or multiple sclerosis, and has also been found to be a method of promoting arousal in multiple sclerosis patients.

Another aspect of the invention provides a pharmaceutical composition comprising a modafinil compound to a patient suffering from attention deficit hyperactivity disorder or multiple sclerosis fatigue symptoms in an amount effective to stimulate activity in nodular papillary neurons of the patient's brain. Method of treating such a patient, comprising administering.

Another aspect of the invention is a pharmaceutical composition as a unit dosage form for use in treating attention deficit hyperactivity disorder in a patient susceptible to or suffering from the development of attention deficit hyperactivity disorder, the composition being administered at periodic administration. One or more unit doses of the modafinil compound include amounts of modafinil compound that are effective to stabilize or ameliorate symptoms of attention deficit hyperactivity disorder in a patient.

Another aspect of the invention is a pharmaceutical composition as a unit dosage form for use in treating fatigue in multiple sclerosis patients, wherein the composition comprises multiple doses of the modafinil compound in the patient at the time of periodic administration. Amount of modafinil compound that is effective to stabilize or ameliorate sclerosis fatigue symptoms.

As disclosed herein and used in the compositions and methods of the invention, the modafinil compound may comprise a racemic mixture and may be in acid form, such as the metabolic acid or benzhydrylsulfinylacetic acid, modulone form of modafinil, Hydroxylated forms, conjugated forms such as modafinil compounds conjugated to proteins, polysaccharides, glucuronides or sulfates, or polymorphs, and compounds containing isomeric substitutions of phenyl groups of modafinil Polymorphic species or analogs of finil, or derivatives of cogeners and prodrugs, particularly agents that stimulate activity in TMN upon administration to a mammal. In a preferred embodiment, the modafinil compound is modafinil. Prodrugs are known in the art as compounds that convert into the active agent (modafinil) in the body of a patient.

Preferably, the compositions and methods disclosed herein are useful in the treatment of mammalian patients, more particularly humans. Because MS and ADHD are known to harass both adults and adolescents or children, the methods and compositions disclosed herein affect this population group. While effective amounts may be provided in mg / day for human oral administration, unless otherwise indicated, the dosage may be determined according to the treatment of a human adult and the dosage for children is appropriately controlled.

It is an object of the present invention to provide a method of treatment comprising an effective amount of modafinil compound for the treatment of ADHD and MS fatigue, preferably an effective amount of about 1 to about 400 mg per day administration. For example, it is known in the art that dosages of about 200 mg / day to about 400 mg / day are effective arousal-promoting doses and such dosages are expected to be useful for the treatment of ADHD and MS fatigue. It is also known that such doses are expected to be useful for the treatment of ADHD and MS fatigue, although doses of about 100 mg / day are low thresholds for arousal-promoting doses. In addition, studies in other cases have shown the beneficial activity of modafinil at sub-wake promotion doses, particularly in improving cognitive function. As such, aspects of the invention provide that an effective amount of modafinil compound for use in the methods disclosed herein is from about 1 mg / day to about 400 mg / day, or from about 100 to about 400 mg, or 1 day About 200 to about 400 mg per administration, or even 200 mg per daily administration. In addition, although not explicitly mentioned, dosages within this range, such as 30 mg, 50 mg, 75 mg, and the like, are understood to be included in that range because they are slightly outside of the stated range limits.

In a preferred embodiment, the composition comprising the modafinil compound is formulated for oral administration, more preferably as a tablet for oral administration. Formulations of modafinil containing tablets are known in the art as described below, which tablets are preferably various such as lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc It may contain inactive ingredients in any combination.

Aspects of the invention may also be described as a therapeutic package for use in or in a patient receiving treatment for attention deficit hyperactivity disorder or multiple sclerosis fatigue, wherein the packaging comprises (1) one or more units Dosage (each unit dose is an amount of modafinil compound such that the one or more unit doses are effective to stabilize or ameliorate symptoms of concentration deficit hyperactivity disorder or multiple sclerosis fatigue in a mammal upon periodic administration. Wherein the unit dose is administered periodically), and (2) a finished pharmaceutical container therefor, the container comprising (a) the unit dose or unit doses and (b) in the treatment of a mammal. And a label indicating the use of the therapeutic package). In a preferred embodiment, the package is suitable for oral administration.

Although the compositions and methods disclosed herein have been described in terms of certain preferred embodiments, it is understood that the modafinil compounds described herein may be administered orally, eg, with an inert diluent or an assimilable edible carrier. The compositions may also be enclosed in hard or soft skin gelatin capsules, compressed into tablets, or mixed directly with food. For oral therapeutic administration, active compounds such as modafinil may be mixed with excipients and ingestable tablets, buccal tablets, oral tablets, capsules, elixirs, suspensions, syrups, although tablets are generally the preferred method of administration of modafinil. , Oblato, or the like. Such compositions and preparations should contain at least 0.1% active compound. The percentages of the compositions and formulations may of course vary and may conveniently be from about 2 to about 60% of the unit weight.

Tablets, oral tablets, pills, capsules and the like may also contain any of the following ingredients: binders such as rubber tragacanth, gum arabic, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; And sweetening agents such as sucrose, lactose or saccharin may be added, or flavoring agents such as peppermint, camellia oil, or cherry flavor may be added. When the dosage unit form is a capsule, it may contain a liquid carrier in addition to the substances of this kind. Various other materials may be present as coatings or to alter the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shirlag, sugar, or both. Syrups or elixirs may contain active compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, dyes and flavorings such as cherry or orange flavors. Of course, the material used to prepare any dosage unit form must be pharmaceutically pure and substantially non-toxic in the amount used. The active compounds can also be incorporated into sustained release formulations and formulations.

In certain embodiments, the disclosed compositions may be formulated for administration by use of a skin patch or transdermal delivery system. Transdermal administration of the modafinil compositions described herein may be accomplished by a number of schemes known in the art. Examples of systems that may be suitable for use with the compositions described herein include US Pat. No. 4,816,252; U.S. Patent 5,122,382; US Patent 5,198,223; U.S. Patent 5,023,084; US Patent 4,906, 169; US Patent 5,145,682; US Patent 4,624,665; US Patent 4,687,481; US Patent 4,834,978; And transdermal administration systems described in US Pat. No. 4,810,499, all of which are incorporated herein by reference.

These methods typically include an adhesive substrate or drug reservoir system, including ethanol, polyethylene glycol 200 dilaurate, isopropyl myristate, glycerol trioleate, linolenic acid saturated ethanol, glycerol monooleate, glycerol monolaurate, n -Decyl alcohols, capric acid, and certain saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides, acetates, diethanolamines and skin penetration enhancers such as N, N-dimethylamide (e.g., US Patent 4,906, 169).

The invention also relates to a method for identifying compounds that stimulate activity in TMN of the posterior hypothalamus. This method involves using standard screening techniques that apply to new discoveries as described above. Thus, the compounds identified by this method and their use as drugs are provided by the present invention in that stimulation in TMN of the posterior hypothalamus will have a beneficial effect on the well-being of the animal or patient to be treated.

The present invention relates to the field of neuropharmacological agents, including agents useful for the treatment of attention deficit hyperactivity disorder and multiple sclerosis related fatigue.

Modafinil is a drug that is active in the central nervous system and has been developed as a treatment for excessive naps associated with sleep attacks. The main pharmacological activity of modafinil is to promote arousal, like amphetamine-based drugs. Modafinil has been described in rat [Touret et al., Neuroscience Letters, 189: 43-46 (1995); Edgar and Seidel, J. Pharmacol. Exp. Ther., 283: 757-69 (1997)], cats [Lin et al., Brain Research, 591: 319-326 (1992)], dogs [Shelton et al., Sleep 18 (10) ): 817-826 (1995)] and non-human primates (DS-93-023, pp. 180-181; Hernant et al., Psychopharmacology, 103: 28-32 (1991)), as well as models that mimic the clinical situation, Sleep apnea (British bulldog respiratory model) [Panckeri et al., 1996] and sleep attacks (sleeping dogs) [Shelton et al., Sleep 18 (10): 817-826 (1995)]. Modafinil is also useful in the treatment of Parkinson's disease (US Pat. No. 5,180,745); in the protection of brain tissue from ischemia (US Pat. No. 5,391,576); in the treatment of urinary incontinence and fecal incontinence (US Pat. No. 5,401,776); and in the central origin It has proven to be a useful drug in sleep apnea treatment (US Pat. No. 5,612,378.) US Pat. No. 5,618,845 demonstrates that modafinil formulations of limited particle size less than about 200 microns are effective. It is demonstrated to be more potent and safer than formulations containing a larger proportion of larger particles.

Several neuroanatomical pathways have been studied for their role in inducing and maintaining arousal, and some studies point to the potential role of the nodular papillary nucleus (TMN) [Sherrin et al., Science 271: 216-219, 1996]. A study by Lin et al. [Proceedings of the National Academy of Science, USA 93: 14128-14133, 1996] demonstrated selective activation of the anterior hypothalamus by modafinil, the authors of which also arouse-promoting It has been demonstrated that administering modafinil to cats at a dose does not cause activation of TMN in the posterior hypothalamus. Similar studies on administering awake-promoted doses of modafinil to rats (Engber et al., Neuroscience, 87: 905-911 (1998)) also found that modafinil-induced arousal was not associated with activation of TMN. Proved. Thus, although activation of TMN is implicated in normal arousal, our researchers clearly suggest that TMN activation is not implicated in modafinil-induced arousal.

The present invention results in part from the discovery that modafinil stimulates activity in TMN of the posterior hypothalamus when administered at an awakening-promoting dose. Modafinil administration in rats reduced the activity of neurons at the hypothalamus lateral lateral lateral optic nerve anterior junction (VLPO), which is known to inhibit the activity of arousal-promoting histamine effector neurons in TMN during sleep. Activation of this histamine agonist pathway by modafinil leads to cortical activation and arousal. Thus, the physiological basis for the wake-promoting action of modafinil seems to be associated with the deinhibition of histamine-activated neurons of TMN by inhibitory action on VLPO. This represents the first pharmacological agent known to cause arousal by activation of TMN. In addition, because modafinil activates the hypothalamus, and because of inhibitory histamine effector neural pathways from hypothalamic synapses on inhibitory gamma-aminobutyric acid (GABA) frontal lobe neurons, we believe that hypothalamic activation is followed by vertebral cells It has been conceived that it contributes to activation and provides a useful mechanism of modafinil in ADHD and MS fatigue [Swanson, J. et al., Current Opinion in Neurobiology, 8: 263-271 (1998); Roelke, U., et al., Neuroobiology, 48: 1566-1571 (1997).

Prior to the invention disclosed or claimed herein, modafinil is known in the art in the form of a therapeutic package and sold under the trade name Provigil ^(R) . Provigil ^(R) is a pharmaceutical product manufactured by Cephalon, Inc. of Westchester, PA, and is also marketed by Cephalon Incorporated. Probigill ^(R) is supplied as a tablet containing 100 mg or 200 mg modafinil. In commercial use, prior art modafinil-containing therapeutic packages are labeled and used in patients with seizures unless otherwise indicated.

Thus, known in the prior art is a therapeutic package which provides as an active ingredient at least one unit dose of modafinil, which is supplied in a finished pharmaceutical container containing said unit dose and also described above. Or contains a label indicating the use of the package in the treatment of the condition. The printed matter attached to the pharmaceutical container indicates that the daily dose of modafinil is 200 mg / day as a once dose in the morning. Although 400 mg / day is also allowed in clinical trials, 200 mg / day is the optimal wake-up facilitation dose in human adults.

All compositions and methods disclosed and claimed herein are feasible without the use of undue experimentation in light of the present disclosure. While the compositions and methods of the invention have been described in terms of preferred embodiments, modifications may be made to the steps and compositions and / or methods of or after the methods described herein, without departing from the spirit, spirit, and scope of the invention. It will be apparent to those skilled in the art that there is. More specifically, it is clear that certain chemically and physiologically relevant agents may be substituted for the agents described herein as long as the same or similar results are achieved. All such similar substitutions and modifications apparent to those skilled in the art are deemed to fall within the spirit, scope and concept of the invention as defined by the appended claims.

The invention is further illustrated by the following examples. The examples are given for illustrative purposes only and should not be construed as limiting the scope or content of the invention.

Experimental Design : In the examples below, rats were sacrificed 2 hours after treatment and brains were analyzed using immunohistochemistry for Fos. In Examples 1 and 2, mice were tested with instruments for EEG (EEG) and EMG (EMG) recordings. In order to avoid handling stress during modafinil or excipient administration, a chronic catheter for modafinil or excipient administration was placed in the peritoneal cavity.

Animal and recording environment : In a room maintained at 21.5-22.5 ° C., lit at 7 am and extinguished at 7 pm, 65 male Sprass-Dauley rats (Harlan) weighing 270-330 g each had a non-pathogenic barrier Live in the facility. Rats were given free access to food and water. At least three days before the experiment, mice were placed in a light-tight and sound-reduced recording chamber (Biocube) in an isolated room. The light intensity was between 100 and 150 lux at medium levels inside each cage. The Institutional Animal Care and Use Committees of Beth Israel Deaconess Medical Center and Harvard Medical School approved all procedures.

Animal Surgery : Four EEG screws (AP: +3, -4 from repair point; RL: +2 from the repair point ) in rats of Examples 1 and 2, slightly in contact with the dura mater, under catcherchlore anesthesia (350 mg / kg intraperitoneal) , -2) and two EMG wires (Roanox, Va., Plastics One) were inserted under the nape muscle. Electrode ceramics were connected to six channel connectors (plastic circles) secured to the skull with dental acrylic. Telemetry temperature transmitters (TA 10TA-F40, St. Paul, Minn., USA) were placed in the peritoneal cavity in all but five mice. To administer the drug without treating the rat, an 80 cm plastic catheter (1 mm inner diameter, Baxter Scientific Products) was inserted into the peritoneal cavity, subcutaneously penetrated into the scalp, and dental acrylic The position was joined and the outside protected by a spring. This intraperitoneal catheter was filled with heparinized pyrofactor-free saline and washed once a week and three days before the experiment. Animals were recovered at least 14 days and then acclimated to the recording cable for 3 days before starting physiological recordings.

Drug Administration : Modafinil (Lot # PA 008; West Chester, Pa., Sepalon, Inc.) was diluted with 0.25% methylcellulose solution in 0.9% pyrogen-free saline (pH = 7.4, Midland, Michigan, USA). It was suspended in Chemical Chemicals Inc. (Dow Chemical Inc.). The drug was administered in a volume of 2.0 ml / kg at a dose of 150 mg / kg. Control animals received an equal volume of methylcellulose excipient. The catheter was then washed with 1 ml 0.9% saline to ensure delivery of the drug in the peritoneal cavity. Red scintillation lamps were used to aid injections performed in the dark.

Histology and immunohistochemistry : Two hours after drug injection, animals are deeply anesthetized with catcherchloral (600 mg / kg intraperitoneal), perfused through the heart with 100 ml 0.9% saline and then 500 ml of phosphate buffer 10% Perfused with formalin (pH 7.0) (Sigma). The brain was removed and postfixed for 4 hours in formalin and then equilibrated with 0.02% sodium azide (Sigma) in 20% sucrose in 0.1M phosphate buffered saline (PBS) at 4 ° C. Brains were split on frozen microtome (1: 5 array, 30 μm) and stored in PBS-azide at 4 ° C. One array from each brain was stained for Fos using the method described previously [Elmquist et al., 1996]. Briefly, the fragments were at 4 ° C. anti-Fos rabbit polyclonal antiserum (Ab-5, Oncogene Research Products, diluted 1: 100,000), 3% donkey serum (Jackson Immuno-Research) ImmunoResearch)) and PBS-azide with 0.25% Triton X-100 (PBT-Az) for 48 hours. The tissues are then rinsed in PBS, incubated for 1 hour at room temperature in biotinylated donkey anti-rabbit IgG (1: 1,000, Jackson Immunoresearch), 1 with peroxidase-conjugated avidin biotin complex (ABC, vector) After incubation for some time, the cells were incubated with 0.05% diaminobenzidine tetrahydrochloride (DAB) and 0.01% H ₂ O ₂ with 1% NiSO ₄ and 0.5% CoCl ₂ to form a black reaction product in the cell nucleus.

Cell count : The pattern of Fos-immunoreactivity was tested for selected brain regions. To quantify this difference, in the region with possible modafinil-induced Fos, testers who were unable to see experimental conditions were allowed to count Fos-IR neurons. For all nuclei, bilateral totals were taken over three consecutive fragments 120 micrometers apart containing the largest nuclear site and averaged six times. In Example 1, the areas involved in behavioral state control: Fos-IR nuclei were counted in the ventral lateral optic nerve anterior segment (VLPO), TMN, ventral capsular region (VTA) and posterior subcortical cortex.

Statistical Analysis : Mann-Whitney rank-sum test using Bonferroni calibration was used to compare Fos-IR cell totals; p was considered significant if less than 0.05.

Example 1

In order to determine the neuronal activation pattern induced by modafinil, modafinil (150 mg / kg) or excipient was administered at midnight, the normal waking period. The data is shown in Table 1 below.

Total cell number of mice treated with modafinil or excipient at midnight. Values are mean ± standard error (values in bold are statistically significantly different from excipients by post-hoc Scheffe test). Excipient Modafinil150 mg / kg Kruskal-Wallis p-value n 6 6 Subcortex 52 ± 13 191 ± 38 0.008 TMN 13 ± 7 46 ± 4 0.005 VTA 8 ± 2 12 ± 3 NS

After administration of modafinil (150 mg / kg), TMN had about four times that of Fos-neuron in control group (Table 1). The neurons of VLPO are active during sleep [Sherin et al., Science 271: 216-9 (1996); Alam et al., Annual Meeting of the Society for Neuroscience, Washington, DC. 1996] It was not surprising that Fos-IR VLPO neurons were rare in all mice because all animals were awake predominantly. Modafinil-treated mice had greater Fos immunoreactivity in the cortex compared to the control. This Fos induction is evident throughout most of the cortex, but in moderate amounts in the frontal and parietal cortex, it is more pronounced in the subject and in the abnormal cortex.

Example 2

In Example 2, modafinil (150 mg / kg) was administered at noon, the normal sleep period. The data is shown in Table 2 below.

Cell totals for mice treated with modafinil or excipient at noon under LD or DD conditions (bold values are statistically different from excipients when using post-hoc Scheffe test) Excipient Modafinil 150 mg / kg Mann-Wittney p value n 6 7 VLPO 52 ± 7 26 ± 3 0.007 TMN 8 ± 4 43 ± 5 0.003

In animals maintained in the normal LD cycle, modafinil (150 mg / kg) administration at noon significantly increased the number of Fos-IR neurons in TMN and decreased VLPO. Modafinil treatment increased the expression of Fos in the frontal and subject cortex.

Claims (32)

Attention deficit hyperactivity, comprising administering a composition comprising a modafinil compound to a patient suffering from or susceptible to attention deficit hyperactivity disorder, in an amount effective to ameliorate or prevent symptoms of attention deficit hyperactivity disorder. Method of treatment of the disorder. A method of treating fatigue associated with multiple sclerosis, comprising administering to a patient suffering from multiple sclerosis fatigue a composition comprising a modafinil compound in an amount effective to ameliorate or prevent the symptoms of multiple sclerosis fatigue. A pharmaceutical composition comprising a modafinil compound comprising administering to the patient an amount effective to stimulate activity in the nodular papillary neurons of the brain of a patient suffering from attention deficit hyperactivity disorder or multiple sclerosis fatigue symptoms. A method of treating a patient suffering from attention deficit hyperactivity disorder or multiple sclerosis fatigue symptoms. At least one unit dose at periodic administration comprises an amount of modafinil compound that is effective to stabilize or ameliorate attention deficit hyperactivity disorder symptoms in a patient suffering from or susceptible to attention deficit hyperactivity disorder, A pharmaceutical composition in unit dosage form for use in treating attention deficit hyperactivity disorder in said patient. For use in treating fatigue in multiple sclerosis patients, at least one unit dose at periodic administration comprises an amount of modafinil compound that is effective to stabilize or ameliorate multiple sclerosis fatigue symptoms in multiple sclerosis patients, Pharmaceutical compositions in unit dosage form. The method of claim 1, wherein the modafinil compound is modafinil. The method of claim 1, wherein the patient is a human adult. The method of claim 1, wherein the patient is a human child. The method of claim 1, wherein said effective amount is from about 1 to about 400 mg per day administration. The method of claim 1, wherein said effective amount is about 100 to about 400 mg per day administration. The method of claim 1, wherein said effective amount is about 200 to about 400 mg per day administration. The method of claim 1, wherein said effective amount is about 200 mg per daily administration. The method of claim 1, wherein the composition comprising the modafinil compound is formulated for oral administration. The method of claim 1, wherein the composition comprising the modafinil compound is formulated as a tablet. The method of claim 14, wherein the tablet contains any combination of lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc. The composition of claim 4 or 5, wherein the modafinil compound is modafinil. 6. The composition of claim 4 or 5, wherein said patient is a human adult or human child. 6. The composition of claim 4 or 5, wherein said effective amount is from about 1 to about 400 mg per day administration. 6. The composition of claim 4 or 5, wherein said effective amount is from about 100 to about 400 mg per day administration. 6. The composition of claim 4 or 5, wherein said effective amount is about 200 to about 400 mg per day administration. 6. The composition of claim 4 or 5, wherein said effective amount is about 200 mg per day administration. 6. The composition of claim 4 or 5, wherein said composition comprising a modafinil compound is formulated for oral administration. The composition of claim 4 or 5, wherein said composition comprising the modafinil compound is formulated as a tablet. 6. A composition according to claim 4 or 5, wherein said tablet contains any combination of lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate or talc. (1) one or more unit doses (each unit dose is modafinil to such an extent that said one or more unit doses are effective to stabilize or ameliorate symptoms of concentration deficit hyperactivity disorder in a mammal upon periodic administration) Contains compound amounts, unit dosages are administered periodically); And (2) a finished pharmaceutical container therefor, the container containing the unit dose or unit doses and a label indicating the use of the therapeutic package in the treatment of the mammal; an attention deficit hyperactivity disorder Therapeutic packaging for or for use in dosing to a mammal being treated for. The therapeutic package of claim 25, wherein the unit dose is suitable for oral administration. (1) one or more unit doses (each unit dose is an amount of modafinil compound such that said one or more unit doses are effective to stabilize or ameliorate the symptoms of multiple sclerosis fatigue in a mammal upon periodic administration. Containing unit doses are administered periodically); And (2) a finished pharmaceutical container therefor, said container containing the unit dose or unit doses and a label indicating the use of the therapeutic package in the treatment of the mammal; Therapeutic packaging for dosing or for use in dosing to a treated mammal. The therapeutic package of claim 27, wherein the unit dose is suitable for oral administration. (a) contacting the nodular papillary nucleus with a test compound; (b) determining the activity of the nodular papillary nucleus, wherein the change in neuronal activity of the nucleus is an indicator of regulatory factors, wherein the compound selectively modulates the activity of the posterior hypothalamic nodular papillary nucleus. Sympathy method. The method of claim 29, wherein said activity is determined by measuring c-fos levels in said neuron. A compound identified by the method of claim 29. 32. A method of treating a patient suffering from or susceptible to excessive nap, attention deficit / hyperactivity disorder, or multiple sclerosis comprising administering an effective amount of a compound of claim 31 to a patient.